This invention is directed to proteinase (protease) inhibitors, and more particularly to thiol sulfonamide inhibitors for matrix metalloproteinases, compositions of proteinase inhibitors, intermediates for the syntheses of proteinase inhibitors, processes for the preparation of proteinase inhibitors and processes for treating pathological conditions associated with pathological matrix metalloproteinase activity.
Connective tissue, extracellular matrix constituents and basement membranes are required components of all mammals. These components are the biological materials that provide rigidity, differentiation, attachments and, in some cases, elasticity to biological systems including human beings and other mammals. Connective tissues components include, for example, collagen, elastin, proteoglycans, fibronectin and laminin. These biochemicals makeup, or are components of structures, such as skin, bone, teeth, tendon, cartilage, basement membrane, blood vessels, cornea and vitreous humor.
Under normal conditions, connective tissue turnover and/or repair processes are controlled and in equilibrium. The loss of this balance for whatever reason leads to a number of disease states. Inhibition of the enzymes responsible loss of equilibrium provides a control mechanism for this tissue decomposition and, therefore, a treatment for these diseases.
Degradation of connective tissue or connective tissue components is carried out by the action of proteinase enzymes released from resident tissue cells and/or invading inflammatory or tumor cells. A major class of enzymes involved in this function are the zinc metalloproteinases (metalloproteases).
The metalloprotease enzymes are divided into classes with some members having several different names in common use. Examples are: collagenase I (MMP-1, fibroblast collagenase; EC 3.4.24.3); collagenase II (MMP-8, neutrophil collagenase; EC 3.4.24.34), collagenase III (MMP-13), stromelysin 1 (MMP-3; EC 3.4.24.17), stromelysin 2 (MMP-10; EC 3.4.24.22), proteoglycanase, matrilysin (MMP-7), gelatinase A (MMP-2, 72 kDa gelatinase, basement membrane collagenase; EC 3.4.24.24), gelatinase B (MMP-9, 92 kDa gelatinase; EC 3.4.24.35), stromelysin 3 (MMP-11), metalloelastase (MMP-12, HME, human macrophage elastase) and membrane MMP (MMP-14). MMP is an abbreviation or acronym representing the term Matrix Metalloprotease with the attached numerals providing differentiation between specific members of the MMP group.
The uncontrolled breakdown of connective tissue by metalloproteases is a feature of many pathological conditions. Examples include rheumatoid arthritis, osteoarthritis, septic arthritis; corneal, epidermal or gastric ulceration; tumor metastasis, invasion or angiogenesis; periodontal disease; proteinuria; Alzheimers Disease; coronary thrombosis and bone disease. Defective injury repair processes also occur. This can produce improper wound healing leading to weak repairs, adhesions and scarring. These latter defects can lead to disfigurement and/or permanent disabilities as with post-surgical adhesions.
Matrix metalloproteases are also involved in the biosynthesis of tumor necrosis factor (TNF), and inhibition of the production or action of TNF and related compounds is an important clinical disease treatment mechanism. TNF-xcex1, for example, is a cytokine that at present is thought to be produced initially as a 28 kD cell-associated molecule. It is released as an active, 17 kD form that can mediate a large number of deleterious effects in vitro and in vivo. For example, TNF can cause and/or contribute to the effects of inflammation, rheumatoid arthritis, autoimmune disease, multiple sclerosis, graft rejection, fibrotic disease, cancer, infectious diseases, malaria, mycobacterial infection, meningitis, fever, psoriasis, cardiovascular/pulmonary effects such as post-ischemic reperfusion injury, congestive heart failure, hemorrhage, coagulation, hyperoxic alveolar injury, radiation damage and acute phase responses like those seen with infections and sepsis and during shock such as septic shock and hemodynamic shock. Chronic release of active TNF can cause cachexia and anorexia. TNF can be lethal.
TNF-xcex1 convertase is a metalloproteinase involved in the formation of active TNF-xcex1. Inhibition of TNF-xcex1 convertase inhibits production of active TNF-xcex1. Compounds that inhibit both MMPs activity have been disclosed in WIPO International Publication Nos. WO 94/24140, WO 94/02466 and WO 97/20824. There remains a need for effective MMP and TNF-xcex1 convertase inhibiting agents. Compounds that inhibit MMPs such as collagenase, stromelysin and gelatinase have been shown to inhibit the release of TNF (Gearing et al. Nature 376, 555-557 (1994), McGeehan et al., Nature 376, 558-561 (1994)).
MMPs are involved in other biochemical processes in mammals as well. Included is the control of ovulation, post-partum uterine involution, possibly implantation, cleavage of APP (xcex2-Amyloid Precursor Protein) to the amyloid plaque and inactivation of xcex11-protease inhibitor (xcex11-PI). Inhibition of these metalloproteases permits the control of fertility and the treatment or prevention of Alzheimers Disease. In addition, increasing and maintaining the levels of an endogenous or administered serine protease inhibitor drug or biochemical such as xcex11-PI supports the treatment and prevention of diseases such as emphysema, pulmonary diseases, inflammatory diseases and diseases of aging such as loss of skin or organ stretch and resiliency.
Inhibition of selected MMPs can also be desirable in other instances. Treatment of cancer and/or inhibition of metastasis and/or inhibition of angiogenesis are examples of approaches to the treatment of diseases wherein the selective inhibition of stromelysin, gelatinase, or collagenase III are the relatively most important enzyme or enzymes to inhibit especially when compared with collagenase I (MMP-1). A drug that does not inhibit collagenase I can have a superior therapeutic profile. Osteoarthritis, another prevalent disease wherein it is believed that cartilage degradation in inflamed joints is at least partially caused by MMP-13 released from cells such as stimulated chrondrocytes, may be best treated by administration of drugs one of whose modes of action is inhibition of MMP-13. See, for example, Mitchell et al., J. Clin. Invest., 97:761-768 (1996) and Reboul et al., J. Clin. Invest., 97:2011-2019 (1996).
Inhibitors of metalloproteases are known. Examples include natural biochemicals such as tissue inhibitor of metalloproteinase (TIMP), xcex12-macroglobulin and their analogs or derivatives. These are high molecular weight protein molecules that form inactive complexes with metalloproteases. A number of smaller peptide-like compounds that inhibit metalloproteases have been described. Mercaptoamide peptidyl derivatives have shown ACE inhibition in vitro and in vivo. Angiotensin converting enzyme (ACE) aids in the production of angiotensin II, a potent pressor substance in mammals and inhibition of this enzyme leads to the lowering of blood pressure. Thiol group-containing amide or peptidyl amide-based metalloprotease (MMP) inhibitors are known as is shown in, for example, WO95/12389, WO96/11209 and U.S. Pat. No. 4,595,700.
It is recognized that a compound that inhibits a known member of the MMP group of enzymes can inhibit members in that group and also new, yet to be discovered, enzymes. Therefore, the skilled person will presume that the novel inhibitors of this invention can be useful in the treatment of the diseases in which known and new MMP enzymes are implicated.
The present invention is directed to a process for treating a mammal having a condition associated with pathological matrix metalloprotease (MMP) activity, as well as to molecules that particularly inhibit the activity of MMP-13.
Briefly, therefore, one embodiment of the present invention is directed to a process for treating a mammal having a condition associated with pathological matrix metalloprotease activity that comprises administering a metalloprotease inhibitor in an effective amount to a host having such a condition. The administered enzyme inhibitor corresponds in structure to one of formulae (I), (II) or (III), below 
where x represents 0, 1 or 2, and W is oxygen or sulfur.
A contemplated R9 group is an alkyl, aryl, alkoxy, cycloalkyl, aryloxy, aralkoxy, aralkyl, aminoalkyl, heteroaryl and N-monosubstituted or N,N-disubstituted aminoalkyl group wherein the substituent(s) on the nitrogen are selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and alkanoyl, or wherein the nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclic or heteroaryl ring.
A contemplated R1 group is linked to the SO2 portion of an inhibitor and is an alkyl, cycloalkyl, heterocycloalkyl, aralkanoylalkyl, arylcarbonylalkyl, hydroxyalkyl, alkanoylalkyl, aralkylaryl, aryloxyalkylaryl, aralkoxyaryl, arylazoaryl, arylhydrazinoaryl, haloalkyl, alkylthioaryl, arylthioalkyl, alkylthioaralkyl, aralkylthioalkyl, or aralkylthioaryl group, the sulfoxide or sulfone of any of those thio substituents, alkylthioalkyl, and preferably aryl and heterocyclic (heteroaryl) rings such as aralkyl, heteroaralkyl, aralkoxyalkyl, aryloxyalkyl, as well as a fused ring structure comprising two or three 5- or 6-membered aryl rings that can be carbocyclic or heterocyclic rings. The aryl (carbocyclic) and heteroaryl substituents of R1 are themselves unsubstituted or substituted with one or two substituents independently selected from among halo, C1-C10 alkyl, C1-C10 alkoxy, nitro, cyano, perfluoroalkyl, trifluoromethylalkyl, hydroxy, thiol, hydroxycarbonyl, aryloxy, arylthio, arylamino, aralkyl, arylcarboxamido, heteroarylcarboxamido, azoaryl, azoheteroaryl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroaralkyl, cycloalkyl, heterocyclooxy, heterocyclothio, heterocycloamino, cycloalkyloxy, cycloalkylthio, cycloalkylamino, heteroaralkoxy, heteroaralkylthio, heteroaralkylamino, aralkoxy, aralkylthio, aralkylamino, heterocyclic, heteroaryl, arylazo, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, alkanoyl, arylcarbonyl, aralkanoyl, alkanoyloxy, aralkanoyloxy, hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkylthio, alkoxycarbonyl, aryloxyalkoxyaryl, arylthioalkylthioaryl, aryloxyalkylthioaryl, arylthioalkoxyaryl, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, amino, alkanoylamino, arylcarbonylamino, aralkanoylamino, heteroarylcarbonylamino, heteroaralkanoylamino, and N-monosubstituted or N,N-disubstituted aminoalkyl wherein the substituent(s) on the nitrogen are selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and alkanoyl, or wherein the nitrogen and two substituents attached thereto together form a 5- to 8-membered heterocyclo or heteroaryl ring.
A contemplated R2 substituent can be hydrogen (hydrido), an alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkynylalkyl, alkenylalkyl, thioalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, aralkoxyalkyl, aminoalkyl, alkoxyalkoxyalkyl, aryloxyalkyl, hydroxyalkyl, hydroxycarbonylalkyl, hydroxycarbonylaralkyl, or N-monosubstituted or N,N-disubstituted aminoalkyl group wherein the substituent(s) on the nitrogen are selected from the group consisting of alkyl, aralkyl, cycloalkyl and alkanoyl, or wherein R2 and the nitrogen to which it is bonded and another substituent (i.e., R2 and R4, or R2 and R6 or R2 and R8) together form a 4- to 8-membered heterocyclo or heteroaryl ring.
Contemplated R3 and R4 groups are independently selected. Those substituents can be hydrogen (hydrido), an alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl, aryloxyalkyl, aralkoxyalkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, hydroxycarbonyl, alkoxycarbonyl, perfluoroalkyl, trifluoromethylalkyl, thioalkyl, alkylthioalkyl, arylthioalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, or a sulfoxide or sulfone of any of the thio substituents, aminocarbonyl, aminocarbonylalkyl, N-monosubstituted or N,N-disubstituted aminocarbonyl or aminocarbonylalkyl group wherein the substituent(s) on the nitrogen are independently selected from among alkyl, aralkyl, cycloalkyl and alkanoyl, or wherein the nitrogen and two substituents attached thereto together form a 5- to 8-membered heterocyclo or heteroaryl ring that can contain one additional heteroatom, or R2 and R4 together with the atoms to which they are attached form a 4- to 8-membered ring (as above), or R3 and R4 together with the atom to which they are attached form a 3- to 8-membered ring or R4 and R8 together with the atoms to which they are attached form a 5- to 8-membered ring.
R5 and R6 substituents are also independently selected. R5 and R6 substituents can be a substituent that constitutes R3 and R4, or R6 and R4 together with atoms to which they are attached form a 4- to 8-membered ring, or R6 and R2 together with the atoms to which they are attached form a 5- to 8-membered ring (as above), or R6 and R8 together with the atoms to which they are attached form a 4- to 8-membered ring, or R5 and R6 together with atom to which they are attached form a 3- to 8-membered ring.
Contemplated R7 and R8 substituents are also independently selected. R7 and R8 substituents can also be a substituent that constitutes R3 and R4, or R8 and R2 together with the atoms to which they are attached form a 6- to 8-membered ring (as above), or R7 and R8 together with the atom to which they are attached form a 3- to 8-membered ring, or R8 and R4 together with the atom to which they are attached form a 5- to 8-membered ring (as above), or R8 and R6 together with the atoms to which they are attached form a 4- to 8-membered ring (as above).
A provision to the above definitions is that no carbon atom is geminally substituted with more than one sulfhydryl group. Additionally, a starred substituent xe2x80x9cRxe2x80x9d groups and xe2x80x9cxxe2x80x9d of formula III are the same as or different from the unstarred xe2x80x9cRxe2x80x9d groups and xe2x80x9cxxe2x80x9d.
The present invention is also directed to a more preferred sub-set of molecules of formulas I, II, and III, above. Here, x is zero so that the mercapto group is bonded directly to the carbon atom that bears the R5 and R6 substituent radicals, which are themselves both hydrido, as is R3. Here, also, R2 is other than hydrogen (hydrido) unless R1 is phenylazophenyl, R1 is an aryl, substituted aryl, heteroaryl, or substituted heteroaryl group containing one 5- or 6-membered ring; i.e. R1 is not a fused aryl ring or heteroaryl group, and a compound of formula III is a homodimer. These preferred compounds are depicted by formulas Ia, IIa, and IIIa, below, and the substituent xe2x80x9cRxe2x80x9d groups and W are as otherwise defined before. 
In most preferred practice, a contemplated inhibitor compound constitutes another sub-set of the compounds of formulas I, II and III. Here, R3, R5 and R6 are again hydrido, the SO2-linked R1 substituent is a 4-substituted phenyl group (PhR11), and W is O. These most preferred compounds are depicted by formulas Ib, IIb and IIIb, below. Specifics of the depicted xe2x80x9cRxe2x80x9d groups are discussed hereinafter. 
Yet another aspect of the invention is directed to a matrix metalloprotease inhibitor corresponding to formula IV, below, 
where R10 is hydrogen (hydrido) or xe2x80x94C(O)xe2x80x94R9, and R1, R2, R3, R4, R5, R6, R9 and x are as defined above, and Y represents hydrogen, halogen, alkyl, alkoxy, nitro, cyano, carboxy or amino.
Among the several benefits and advantages of the present invention are the provision of compounds and compositions effective as inhibitors of matrix metalloproteinase activity, the provision of such compounds and compositions that are effective for the inhibition of metalloproteinases implicated in diseases and disorders involving uncontrolled breakdown of connective tissue.
More particularly, a benefit of this invention is the provision of a compound and composition effective for inhibiting metalloproteinases, particularly MMP-13, associated with pathological conditions such as, for example, rheumatoid arthritis, osteoarthritis, septic arthritis, corneal, epidermal or gastric ulceration, tumor metastasis, invasion or angiogenesis, periodontal disease, proteinuria, Alzheimer""s Disease, coronary thrombosis and bone disease.
An advantage of the invention is the provision of a method for preparing such compositions. Another benefit is the provision of a method for treating a pathological condition associated with abnormal matrix metalloproteinase activity.
Another advantage is the provision of compounds, compositions and methods effective for treating such pathological conditions by selective inhibition of a metalloproteinase, MMP-13, associated with such conditions with minimal side effects resulting from inhibition of other proteinases whose activity is necessary or desirable for normal body function.
Still further benefits and advantages of the invention will be apparent to the skilled worker from the disclosure that follows.
In accordance with the present invention, it has been discovered that certain thiol sulfonamides are effective for inhibition of matrix metalloproteinases (xe2x80x9cMMPsxe2x80x9d) believed to be associated with uncontrolled or otherwise pathological breakdown of connective tissue. In particular, it has been found that these certain thiol sulfonamides are effective for inhibition of collagenase III (MMP-13), which can be particularly destructive to tissue if present or generated in abnormal quantities or concentrations, and thus exhibit a pathological activity.
Moreover, it has been discovered that many of these thiol sulfonamides are selective in the inhibition of MMP-13, as well as other MMPs associated with diseased conditions without excessive inhibition of other collagenases essential to normal bodily function such as tissue turnover and repair. More particularly, it has been found that particularly preferred the thiol sulfonamides of the invention are particularly active in inhibiting of MMP-13, while being selective for MMP-13, in having a limited or minimal effect on MMP-1. This point is discussed in detail hereinafter and is illustrated in several examples.
One embodiment of the present invention is directed to a process for treating a mammal having a condition associated with pathological matrix metalloprotease activity. That process comprises administering a metalloprotease inhibitor in an effective amount to a host having such a condition. The administered enzyme inhibitor corresponds in structure to one of formulas (I), (II) or (III), below 
where x represents 0, 1 or 2, and W is oxygen or sulfur.
A contemplated R9 group is an alkyl, aryl, alkoxy, cycloalkyl, aryloxy, aralkoxy, aralkyl, aminoalkyl, heteroaryl and N-monosubstituted or N,N-disubstituted aminoalkyl group wherein the substituent(s) on the nitrogen are selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and alkanoyl, or wherein the nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring.
A contemplated R1 group is linked to the SO2 portion of an inhibitor and is an alkyl, cycloalkyl, heterocycloalkyl, aralkanoylalkyl, arylcarbonylalkyl, hydroxyalkyl, alkanoylalkyl, aralkylaryl, aryloxyalkylaryl, aralkoxyaryl, arylazoaryl, arylhydrazinoaryl, haloalkyl, alkylthioaryl, arylthioalkyl, alkylthioaralkyl, aralkylthioalkyl, or aralkylthioaryl group, the sulfoxide or sulfone of any of those thio substituents, alkylthioalkyl, and preferably aryl (carbocyclicaryl) and heteroaryl rings such as aralkyl, heteroaralkyl, aralkoxyalkyl, aryloxyalkyl, as well as a fused ring structure comprising two or three 5- or 6-membered aryl rings that can be carbocyclic or heterocyclic rings. The aryl and heteroaryl substituents of which R1 can be comprised are unsubstituted or preferably substituted with one (preferably) or two substituents independently selected from among halo, C1-C10 alkyl, C1-C10 alkoxy, nitro, cyano, perfluoroalkyl, trifluoromethylalkyl, hydroxy, thiol, hydroxycarbonyl, aryloxy, arylthio, arylamino, aralkyl, arylcarboxamido, heteroarylcarboxamido, azoaryl, azoheteroaryl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroaralkyl, cycloalkyl, heterocyclooxy, heterocyclothio, heterocycloamino, cycloalkyloxy, cycloalkylthio, cycloalkylamino, heteroaralkoxy, heteroaralkylthio, heteroaralkylamino, aralkoxy, aralkylthio, aralkylamino, heterocyclic, heteroaryl, arylazo, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, alkanoyl, arylcarbonyl, aralkanoyl, alkanoyloxy, aralkanoyloxy, hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkylthio, alkoxycarbonyl, aryloxyalkoxyaryl, arylthioalkylthioaryl, aryloxyalkylthioaryl, arylthioalkoxyaryl, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, amino, alkanoylamino, arylcarbonylamino, aralkanoylamino, heteroarylcarbonylamino, heteroaralkanoylamino, and N-monosubstituted or N,N-disubstituted aminoalkyl wherein the substituent(s) on the nitrogen are selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and alkanoyl, or wherein the nitrogen and two substituents attached thereto together form a 5- to 8-membered heterocyclo or heteroaryl ring.
A contemplated R2 substituent can be hydrogen (hydrido), an alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkynylalkyl, alkenylalkyl, thioalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, aralkoxyalkyl, aminoalkyl, alkoxyalkoxyalkyl, aryloxyalkyl, hydroxyalkyl, hydroxycarbonylalkyl, hydroxycarbonylaralkyl, or N-monosubstituted or N,N-disubstituted aminoalkyl group wherein the substituent(s) on the nitrogen are selected from the group consisting of alkyl, aralkyl, cycloalkyl and alkanoyl, or wherein R2 and the nitrogen to which it is bonded and another substituent (i.e., R2 and R4, or R2 and R6, or R2 and R8) together form a 4- to 8-membered heterocyclo or heteroaryl ring.
Contemplated R3 and R4 groups are independently selected. Those substituents can be hydrogen (hydrido), an alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl, aryloxyalkyl, aralkoxyalkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, hydroxycarbonyl, alkoxycarbonyl, perfluoroalkyl, trifluoromethylalkyl, thioalkyl, alkylthioalkyl, arylthioalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, or a sulfoxide or sulfone of any of the thio substituents, aminocarbonyl, aminocarbonylalkyl, N-monosubstituted or N,N-disubstituted aminocarbonyl or aminocarbonylalkyl group wherein the substituent(s) on the nitrogen are independently selected from among alkyl, aralkyl, cycloalkyl and alkanoyl, or wherein the nitrogen and two substituents attached thereto together form a 5- to 8-membered heterocyclo or heteroaryl ring that can contain one additional heteroatom, or R2 and R4 together with the atoms to which they are attached form a 4- to 8-membered ring (as above), or R3 and R4 together with the atom to which they are attached form a 3- to 8-membered ring, or R4 and R6 together with the atoms to which they are attached form a 4- to 8-membered ring, or R4 and R8 together with the atoms to which they are attached form a 5- to 8-membered ring.
R5 and R6 substituents are also independently selected. R5 and R6 substituents can be a substituent that constitutes R3 and R4. Alternatively, R6 and R4 together with atoms to which they are attached form a 4- to 8-membered ring, or R6 and R2 together with the atoms to which they are attached form a 5- to 8-membered ring (as above), or R6 and R8 together with the atoms to which they are attached form a 4- to 8-membered ring, or R5 and R6 together with atom to which they are attached form a 3- to 8-membered ring.
Contemplated R7 and R8 substituents are also independently selected. R7 and R8 substituents can also be a substituent that constitutes R3 and R4. Alternatively, R8 and R2 together with the atoms to which they are attached form a 6- to 8-membered ring (as above), or R7 and R8 together with the atom to which they are attached form a 3- to 8-membered ring, or R8 and R4 together with the atom to which they are attached form a 5- to 8-membered ring (as above), or R8 and R6 together with the atoms to which they are attached form a 4- to 8-membered ring (as above).
A provision to the above definitions is provided that no carbon atom is geminally substituted with more than one sulfhydryl group. In addition, starred substituent xe2x80x9cRxe2x80x9d groups and xe2x80x9cxxe2x80x9d of formula III are the same as or different from the unstarred xe2x80x9cRxe2x80x9d groups and xe2x80x9cxxe2x80x9d.
In generally increasing order of preference, the following paragraphs summarize the substituents which may most advantageously constitute each of R1 through R10, as well as W and x.
R1 represents an aryl-C1-C10-alkyl or heteroaryl-C1-C10-alkyl, wherein the aryl or heteroaryl ring can optionally be substituted by one or more of the following substituents: C1-C10 alkyl, C1-C10 alkoxy, aryloxy, heteroaryloxy, aryl, heteroaryl, aralkoxy, heteroaralkoxy, C1-C10 alkylthio, arylthio, heteroarylthio.
R1 represents a single aryl or heteroaryl ring, wherein the single aryl or heteroaryl ring can optionally be substituted by one or more of the following substituents: C1-C6 alkyl, C1-C6 alkoxy, arylcarboxamido, heteroarylcarboxamido,arylazo, heteroarylazo, aryloxy, heteroaryloxy, aryl, heteroaryl, aralkoxy, heteroaralkoxy, C1-C6 alkylthio, arylthio, heteroarylthio in which each ring-containing substituent itself contains a single ring.
R1 represents a 6-membered aryl ring, wherein the aryl ring can optionally be substituted in the para-position (4-position) by one of the following substituents: C1-C6 alkyl, C1-C6 alkoxy, arylcarboxamido, heteroarylcarboxamido, arylazo, heteroarylazo, aryloxy, heteroaryloxy, aryloxy, heteroaryloxy, aryl, heteroaryl, aralkoxy, heteroaralkoxy, C1-C6 alkylthio, arylthio, heteroarylthio in which each ring-containing substituent itself contains a single ring.
R1 represents a 6-membered aryl ring, wherein the aryl ring is substituted in the para-position by C1-C6 alkyl, C1-C6 alkoxy arylcarboxamido, arylazo, aryloxy, arylthio and aryl in which each ring-containing substituent itself contains a single ring.
R1 represents phenyl, wherein the phenyl ring is substituted in the para-position by n-propyl, n-butyl, n-pentyl, n-hexyl, isobutyl, isoamyl, ethoxy, n-propyloxy, n-butoxy, n-pentyloxy, n-hexyloxy, isobutoxy, phenoxy, thiophenoxy (phenylthio), phenyl, azophenyl or benzamido, in which the para-substituted R1 phenyl substituent can itself optionally contain a meta- or para-substituent, or both containing one atom or a chain of no more than five atoms other than hydrogen.
R2 Preferences:
R2 represents hydrogen, C1-C6 alkyl, aralkyl, heteroaralkyl, cycloalkylalkyl having 4-8 carbons in the ring and 1-3 carbons in the alkyl chain, heterocycloalkylalkyl in which 4-8 atoms are in the ring, one or two of which atoms can be nitrogen, oxygen or sulfur and in which the alkyl chain contains 1-3 carbons, C1-C5 alkyl substituted by hydroxycarbonyl, amino, mono-substituted amino and di-substituted amino, wherein the substituents on nitrogen are chosen from C1-C4 alkyl, aralkyl, C5-C8 cycloalkyl and C1-C6 alkanoyl groups, or wherein the two substituents and the nitrogen to which they are attached when taken together form a 5- to 8-membered heterocyclo or heteroaryl ring.
R2 represents hydrogen, C1-C6 alkyl, aralkyl, heteroaralkyl, cycloalkylalkyl having 4-8 carbons in the ring and 1-3 carbons in the alkyl chain, heterocycloalkylalkyl in which 4-8 atoms are in the ring, one or two of which atoms can be nitrogen, oxygen or sulfur and in which the alkyl chain contains 1-3 carbons.
R2 represents hydrogen or C1-C6 alkyl.
R2 represents hydrogen, methyl, ethyl, n-propyl, n-butyl, isobutyl.
R2 represents carbocyclic aralkyl or heteroaralkyl as discussed above.
R2 represents benzyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-thiazolylmethyl, 4-thiazolylmethyl, 5-thiazolylmethyl.
R2 represents cycloalkylalkyl having 4-8 carbons in the ring and 1-3 carbons in the alkyl chain, heterocycloalkylalkyl in which 4-8 atoms are in the ring, one or two of which atoms can be nitrogen, oxygen or sulfur and in which the alkyl chain contains 1-3 carbons.
R2 represents cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl.
R2 represents alkyl substituted by hydroxycarbonyl, amino, mono-substituted amino and di-substituted amino, wherein the substituents on the amino nitrogen are chosen from C1-C6 alkyl, aralkyl, C5-C8 cycloalkyl and C1-C6 alkanoyl, or wherein the two substituents and the nitrogen to which they are attached when taken together form a 5- to 8-membered heterocyclo or heteroaryl ring containing zero or one additional hetero atoms that are nitrogen, oxygen or sulfur.
R2 represents C1-C5 alkyl substituted by hydroxycarbonyl.
R2 represents 5-pentanoic acid, 4-n-butanoic acid, 3-propanoic acid or 2-ethanoic acid.
R2 represents hydrido, C1-C6 alkyl, C2-C4 alkyl substituted by amino, mono-substituted amino or di-substituted amino, wherein the substituents on nitrogen are chosen from C1-C6 alkyl, aralkyl, C5-C8 cycloalkyl and C1-C6 alkanoyl, or wherein the two substituents and the nitrogen to which they are attached when taken together form a 5- to 8-membered heterocyclo or heteroaryl ring containing zero or one additional hetero atoms that are nitrogen, oxygen or sulfur, a C1-C4 alkylaryl or C1-C4 alkylheteroaryl group having a single ring.
R2 represents methyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, N,N-dimethyl-2-aminoethyl, 2-(4-morpholino)ethyl, 2-(1-piperidino)ethyl, 2-(1-pyrrolidino)ethyl.
R3 and R4 Preferences:
R3 and R4 independently represent hydrogen, hydroxycarbonyl, aminocarbonyl, C1-C6 alkyl, aralkyl, aryl, heteroaryl, C5-C8 cycloalkyl, heteroaralkyl, cycloalkylalkyl having 4-8 carbons in the ring and 1-3 carbons in the alkyl chain.
R3 is hydrido, and R4 is hydroxycarbonyl, aminocarbonyl or C1-C6 alkyl.
R3 and R4 independently represents hydrogen, aminocarbonyl, methyl.
R3 is hydrido and R4 represents methyl.
R3 is hydrido and R4 represents hydroxycarbonyl or aminocarbonyl.
R3 represents hydrido and R4 represents aminocarbonyl (carbamyl) or methyl.
R5 and R6 Preferences:
R5 and R6 independently represent hydrogen (hydrido), hydroxycarbonyl, aryl, heteroaryl, C1-C6 alkyl.
R5 and R6 are both hydrido.
R7 and R8 Preferences:
R7 and R8 independently represent hydrogen, hydroxycarbonyl, C1-C6 alkyl.
x Preferences:
x is preferably zero.
W is preferably oxygen (O).
R9 Preferences:
R9 represents C1-C6 alkyl, aryl, C1-C6 alkoxy, heteroaryl, amino C1-C6 alkyl, N-monosubstituted amino C1-C6 alkyl and N,N-disubstituted amino C1-C6 alkyl, wherein the substituents on nitrogen are chosen from C1-C6 alkyl, aralkyl, C5-C8 cycloalkyl and C1-C6 alkanoyl, or wherein the two substituents and the nitrogen to which they are attached when taken together form a 5- to 8-membered heterocyclo or heteroaryl ring.
R9 represents C1-C6 alkyl, C5-C8 cycloalkyl, aryl, C1-C6 alkoxy, heteroaryl, amino C1-C6 alkyl, N-monosubstituted amino C1-C6 alkyl and N,N-disubstituted amino C1-C6 alkyl, wherein the substituents on nitrogen are chosen from C1-C6 alkyl, aralkyl, C5-C8 cycloalkyl and C1-C6 alkanoyl, or wherein the two substituents and the nitrogen to which they are attached when taken together form a 5- to 8-membered heterocyclo or heteroaryl ring.
R9 represents C1-C6 alkyl, C1-C6 alkoxy, a single-ringed aryl or heteroaryl.
R9 represents methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl.
R9 represents a 3- to 8-membered cycloalkyl ring.
R9 represents cyclohexyl and cyclopentyl.
R9 represents aryl or heteroaryl.
R9 represents phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, thiophene-2-yl, 3-thiophene-3-yl.
R9 represents C1-C6 alkoxy.
R9 represents methoxy and ethoxy.
Starred substituents, R*, and x* are preferably the same as unstarred substituents, R, and x so that a compound of formula III is homodimer.
In particularly preferred practice, an SO2-linked R1 substituent is an aryl or heteroaryl group that is a 5- or 6-membered single-ring, and is itself substituted with one other single-ringed aryl or heteroaryl group or, with an alkyl or alkoxy group containing an umbranched chain of 3 to about 7 carbon atoms, a phenoxy group, a thiophenoxy [C6H5xe2x80x94Sxe2x80x94] group, a phenylazido [C6H5xe2x80x94N2xe2x80x94] group or a benzamido [xe2x80x94NHC(O)C6H5] group. The SO2-linked single-ringed aryl or heteroaryl R1 group is substituted at its own 4-position when a 6-membered ring and at its own 3-position when a 5-membered ring.
The R1 group""s substituent single-ringed aryl or heteroaryl, phenoxy, thiophenoxy, phenylazo or benzamido group is unsubstituted or can itself be substituted at the 4-position when a 6-membered ring or the 3-position when a 5-membered ring. The 4- and 3-positions of rings discussed here are numbered from the sites of substituent bonding as compared to formalized ring numbering positions used in heteroaryl nomenclature. Here, single atoms such as halogen moieties or substituents that contain one to a chain of about five atoms other than hydrogen such as C1-C4 alkyl, C1-C4 alkoxy or carboxyethyl groups can be used. Exemplary substituted SO2-linked R1 substituents include biphenyl, 4-phenoxyphenyl, 4-thiophenoxyphenyl, 4-butoxyphenyl, 4-pentylphenyl, 4-(4xe2x80x2-dimethylaminophenyl)azophenyl, and 2-[(2-pyridyl)-5-thienyl].
When examined along its longest chain of atoms, an R1 substituent including its own substituent has a total length of greater than a saturated chain of four carbon atoms and less than a saturated chain of about 18 and preferably about 12 carbon atoms, even though many more atoms may be present in ring structures or substituents. This length requirement is discussed further below.
Looked at more generally, and aside from specific moieties from which it is constructed, a particularly preferred R1 radical (group or moiety) has a length greater than that of an butyl group. Such an R1 radical also has a length that is less than that of a stearyl (octadecyl) group. That is to say that a particularly preferred R1 is a radical having a length greater than that of a saturated four carbon chain, and shorter than that of a saturated eighteen carbon chain, and more preferably, a length greater than that of a pentyl group and less than that of a lauryl group.
The radical chain lengths are measured along the longest linear atom chain in the radical, and each atom in the chain, e.g. oxygen or nitrogen, is presumed to be carbon for ease in calculation. Such lengths can be readily determined by using published bond angles, bond lengths and atomic radii, as needed, to draw and measure a staggered chain, or by building models using commercially available kits whose bond angles, lengths and atomic radii are in accord with accepted, published values. Radical lengths can also be determined somewhat less exactly by assuming that all atoms have bond lengths saturated carbon, that unsaturated bonds have the same lengths as saturated bonds and that bond angles for unsaturated bonds are the same as those for saturated bonds, although the above-mentioned modes of measurement are preferred.
In addition, a particularly preferred R1 group when rotated about an axis drawn through the SO2-bonded 1-position and the 4-position of a 6-membered ring or the SO2-bonded position and substituent-bonded 3- or 5-position of a 5-membered ring defines a three-dimensional volume whose widest dimension has the width of about one phenyl ring to about three phenyl rings in a direction transverse to that axis to rotation.
As a consequence of these length and width requirements, R1 substituents such as 4-(phenyl)phenyl[biphenyl], 4-(4xe2x80x2-methoxyphenyl)phenyl, 4-(phenoxy)phenyl, 4-(thiophenyl)phenyl[4-(phenylthio)phenyl], 4-(azophenyl)phenyl and 4-(benzamido)phenyl are particularly preferred R1 substituents.
One sub-set of particularly preferred MMP-13 inhibitor compounds useful in a before-described process has structures depicted by formulas Ia, IIa and IIIa, below. 
In a particularly preferred compound of the above structural formulas, the configuration about the R4-containing carbon atom is that of a naturally-occurring amino acid. The substituent groups are discussed below for these compounds.
An R1 group represents a single aryl or heteroaryl ring, wherein the single aryl ring is unsubstituted or can optionally be substituted by one or more of the following substituents: C1-C6 alkyl, C1-C6 alkoxy, aryloxy, heteroaryloxy, aryl, heteroaryl, aralkoxy, heteroaralkoxy, C1-C6 alkylthio, arylthio, heteroarylthio in which each ring-containing substituent itself contains a single ring.
A single-ringed aryl or heteroaryl group is 5- or 6-membered, and is itself preferably substituted at its own 4-position when a 6-membered ring and at its own 3-position when a 5-membered ring with a substituent selected from the group consisting of one other single-ringed aryl or hetroaryl group, an alkyl or alkoxy group containing an umbranched chain of 3 to about 7 carbon atoms, a phenoxy group, a thiophenoxy group, a phenylazo group or a benzamido group.
R2 represents hydrido, C1-C6 alkyl, C2-C4 alkyl substituted by amino, mono-substituted amino or di-substituted amino, wherein the substituents on nitrogen are chosen from C1-C6 alkyl, aralkyl, C5-C8 cycloalkyl and C1-C6 alkanoyl, or wherein the two substituents and the nitrogen to which they are attached when taken together form a 5- to 8-membered heterocyclo or heteroaryl ring containing zero or one additional hetero atoms that are nitrogen, oxygen or sulfur, a C1-C4 alkylaryl or C1-C4 alkylheteroaryl group having a single ring.
An R4 group is hydroxyxcarbonyl, aminocarbonyl or C1-C6 alkyl.
W is sulfur or oxygen, but preferably oxygen (O).
An R9 group represents a C1-C6 alkyl group, C1-C6 alkoxy group, or a single-ringed carbocyclic aryl or heteroaryl group.
A most preferred MMP-13 inhibitor sub-set of compounds useful in a before-described process also preferably has the configuration of a naturally-occurring amino acid, and corresponds to the structures depicted by formulas Ib, IIb and IIIb, below. 
The substituents of these most preferred MMP-13 inhibitor compounds are as follows:
An R4 group is C1-C6 alkyl, and particularly methyl, or aminocarbonyl [xe2x80x94C(O)NH2].
An R2 group is C1-C6 alkyl and particularly methyl, a C2-C3 alkyl cycloamino group having five or six atoms in the ring and zero or one additional heteroatom that is oxygen or nitrogen, and C1-C4 alkyl single-ringed aryl or heteroaryl, wherein the single heteroaryl ring contains one or two nitrogen atoms. Exemplary most preferred substituents in addition to methyl include 2-(4-morpholino)ethyl, 2-(1-piperidino)ethyl, 2-(1-pyrrolidino)ethyl and (3-pyridyl)methyl. Hydrogen (hydrido) can also be a most preferred R2 group as is discussed below.
The sulfonyl group (xe2x80x94SO2xe2x80x94) of a most preferred sub-set of inhibitor compounds is linked to a phenyl group (Ph), which itself is substituted at the 4-position by a substituent denominated R11 that together with the phenyl group is referred to as PhR11. A 4-substituted phenyl group substituent, R11, can be C3-C8 alkoxy such as butoxy, C3-C8 alkyl such as pentyl, as well as phenoxy, thiophenoxy (phenylthio), benzamido, phenylazo or phenyl.
An R11 6-membered ring-containing substituent group can itself also be substituted in a 3-(meta) or 4-(para-) position, or both, with a halogen (fluorine, chlorine, bromine or iodine), a C1-C4 alkoxy group such as methoxy or isopropoxy, a C1-C4 alkyl group such as methyl, a two or three carbon-containing carboxyl group such as carboxymethyl or carboxyethyl an amine, or a mono- or di-C1-C4 alkyl-substituted amine such as dimethyl amino. A 3,4-methylenedioxy substituent is a contemplated 3,4-substituent, whereas methyl is a contemplated 3-substituent. A substituent of such a R11 ring para substituent has one atom or a longest chain of up to five atoms, excluding hydrogen.
R9 represents a C1-C6 alkyl group, a C1-C6 alkoxy group, a single-ringed carbocyclic aryl or heteroaryl group, and more particularly, a phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, thiophene-2-yl, 3-thiophene-3-yl, methyl, ethyl, methoxy or ethoxy group.
With respect to compounds of the formula 
R10 is hydrogen (hydrido) or xe2x80x94C(O)xe2x80x94R9, and R1, R2, R3, R4, R5, R6, R9 and x are as defined above, and Y represents hydrogen, halogen, alkyl, alkoxy, nitro, cyano, carboxy or amino.
In particularly preferred and most preferred practice, the substituent xe2x80x9cRxe2x80x9d groups and x are as they have been previously described in regard to formulas Ia-IIIa and Ib-IIIb, respectively, except that R3 and R4 are both hydrido in most preferred compounds. Additionally, x is zero so that R5 and R6 and the carbon to which they are bonded are absent, Y is hydrogen, and the sulfur atom bonded to the depicted phenyl ring is linked ortho to the sulfonamide-bearing carbon atom. It is thus seen that particularly preferred and most preferred compounds of formula IV constitute compounds of formulas I and II in which x is one, and the R6 and R8 substituents together with the atoms to which they are attached form a 6-membered, aromatic ring.
A particularly or most preferred R1 group is a radical having a length greater than that of a saturated four carbon chain, and shorter than that of a saturated eighteen carbon chain. When rotated about an axis drawn through the SO2-bonded R1 group 1-position and the 4-position of a 6-membered ring or the SO2-bonded position and substituent-bonded 3- or 5-position of a 5-membered R1 ring, the substituent defines a three-dimensional volume whose widest dimension has the width of about one phenyl ring to about three phenyl rings in a direction transverse to that axis to rotation.
More specifically, an SO2-linked R1 substituent is an aryl or heteroaryl group that is a 5- or 6-membered single-ring, and is itself substituted with one other single-ringed aryl or heteroaryl group or, with an alkyl or alkoxy group containing an umbranched chain of 3 to about 7 carbon atoms, a phenoxy group, a thiophenoxy [C6H5xe2x80x94Sxe2x80x94] group, a phenylazido [C6H5xe2x80x94N2xe2x80x94] group or a benzamido [xe2x80x94NHC(O)C6H5] group. The SO2-linked single-ringed aryl or heteroaryl R1 group is substituted at its own 4-position when a 6-membered ring and at its own 3-position when a 5-membered ring
R2 represents hydrido, C1-C6 alkyl, C2-C4 alkyl substituted by amino, mono-substituted amino or di-substituted amino, wherein the substituents on nitrogen are chosen from C1-C6 alkyl, aralkyl, C5-C8 cycloalkyl and C1-C6 alkanoyl, or wherein the two substituents and the nitrogen to which they are attached when taken together form a 5- to 8-membered heterocyclo or heteroaryl ring containing zero or one additional hetero atoms that are nitrogen, oxygen or sulfur, a C1-C4 alkylaryl or C1-C4 alkylheteroaryl group having a single ring.
An R3 group is hydrido, and R4 is hydroxyxcarbonyl, aminocarbonyl or C1-C6 alkyl. Again, R3 and R4 are both hydrido in most preferred compounds.
An R9 group represents C1-C6 alkyl, C1-C6 alkoxy, a single-ringed carbocyclic aryl or heteroaryl, and more particularly, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, thiophene-2-yl, 3-thiophene-3-yl, methyl, ethyl, methoxy and ethoxy.
Particularly preferred and most preferred compounds correspond to formulas IVa, IVb, IVc and IVd that are shown below: 
The compounds described herein are useful in a process described herein in that such compounds can inhibit the activity of MMP-13. A particularly preferred compound inhibits the enzyme with an IC50 value of about 1000 nm or less in the in vitro assay discussed hereinafter. A most preferred compound exhibits an IC50 value in that assay of about 20 nm or less, with some compounds exhibiting values of about 1 nm or less.
In addition, while being highly active against MMP-13, selectivity of inhibitory activity toward MMP-1 is also exhibited by many of these particularly preferred and most preferred compounds. That is, many compounds exhibit little or no inhibition in the in vitro assay against MMP-1 so that IC50 values are often found to be several thousand to greater than 10,000 nm toward MMP-1. Exemplary ratios of IC50 values toward MMP-1 and MMP-13 (IC50 MMP-1/IC50 MMP-13) can range from about 5 to about 20,000, with most preferred compounds exhibiting ratios of about 500 to about 20,000. Inhibition data for several exemplary compounds are provided in a table hereinafter.
A contemplated inhibitor compound is used for treating a host mammal such as a mouse, rat, rabbit, dog, horse, primate such as a monkey, chimpanzee or human that has a condition associated with pathological matrix metalloprotease activity.
Also contemplated is use of a contemplated metalloprotease inhibitor compound in the treatment of a disease state that can be affected by the activity of metalloproteases TNF-xcex1 convertase. Exemplary of such disease states are the acute phase responses of shock and sepsis, coagulation responses, hemorrhage and cardiovascular effects, fever and inflammation, anorexia and cachexia.
In treating a disease condition associated with pathological matrix metalloproteinase activity, a contemplated MMP inhibitor compound can be used in the form of an amine salt derived from an inorganic or organic acid. Exemplary salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, mesylate and undecanoate.
Also, a basic nitrogen-containing group can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibuytl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others to provide enhanced water-solubility. Water or oil-soluble or dispersible products are thereby obtained as desired. The salts are formed by combining the basic compounds with the desired acid.
Other compounds useful in this invention that are acids can also form salts. Examples include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases or basic quaternary ammonium salts.
In some cases, the salts can also be used as an aid in the isolation, purification or resolution of the compounds of this invention.
Total daily dose administered to a host mammal in single or divided doses can be in amounts, for example, for 0.001 to 30 mg/kg body weight daily and more usually 0.01 to 10 mg. Dosage unit compositions can contain such amounts or submultiples thereof to make up the daily dose. A suitable dose can be administered, in multiple sub-doses per day. Multiple doses per day can also increase the total daily dose should this be desired by the person prescribing the drug.
The dosage regimen for treating a disease condition with a compound and/or composition of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex, diet and medical condition of the patient, the severity of the disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized and whether the compound is administered as part of a drug combination. Thus, the dosage regimen actually employed can vary widely and therefore can deviate from the preferred dosage regimen set forth above.
A compound useful in the present invention can be formulated as a pharmaceutical composition. Such a composition can then be administered orally, parenterally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration can also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques. Formulation of drugs is discussed in, for example, Hoover, John E., Reminqton""s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.; 1975 and Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer""s solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Dimethyl acetamide, surfactants including ionic and non-ionic detergents, polyethylene glycols can be used. Mixtures of solvents and wetting agents such as those discussed above are also useful.
Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter, synthetic mono- di- or triglycerides, fatty acids and polyethylene glycols that are sold at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
Solid dosage forms for oral administration can include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds of this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, the compounds can be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets can contain a controlled-release formulation as can be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. In the case of capsules, tablets, and pills, the dosage forms can also comprise buffering agents such as sodium citrate, magnesium or calcium carbonate or bicarbonate. Tablets and pills can additionally be prepared with enteric coatings.
For therapeutic purposes, formulations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions can also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending upon the mammalian host treated and the particular mode of administration.
Certain compounds of this invention can serve as prodrugs to other compounds of this invention. Prodrugs are drugs that can be chemically converted in vivo or in vitro by biological systems into an active derivative or derivatives. An example from this invention are drugs of formula II (IIa or IIb) where the acyl group is hydrolyzed to a compound of formula I (or Ia or Ib). An additional example is where a disulfide of this invention is reduced to its thiol product or, in some cases, converted into an active mixed disulfide.
Table 1 through Table 80, below, show several series of compounds useful in this invention. Each case, class or group of compounds is illustrated by a generic formula, or formulae, followed by a series of preferred moieties or groups that constitute various substituents that can be attached at the position clearly shown in the generic structure. The generic symbols, e.g., R1, R2 and the like, are as defined before, except that R3 of the following tables corresponds to particularly and must preferred R4 discussed previously. This system is well known in the chemical communication arts and is widely used in scientific papers and presentations. For example in Table 1, R2 is the variable group with the structural variables that can substitute for R2 shown in the balance of the table. There are 40 R2 groups (including hydrogen) shown that are used to represent, in a non-limiting manner, 40 distinct compounds. In a similar manner, Table 43 for example, illustrates a compound with a generic structure containing two variable groups. The groups are R1 and R2. Thus, this example shows a matrix of 12 R1 groups and 10 R2 groups (including hydrogen) that represent 120 non-limiting compounds of this invention that can be prepared.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In the written descriptions of molecules and groups, molecular descriptors can be combined to produce words or phrases that describe structural groups or are combined to describe structural groups. Such descriptors are used in this document. Common illustrative examples include such terms as aralkyl (or arylalkyl), heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, aralkoxyalkoxycarbonyl and the like. A specific example of a compound encompassed with the latter descriptor aralkoxyalkoxycarbonyl is C6H5xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94(Cxe2x95x90O)xe2x80x94 wherein C6H5xe2x80x94 is phenyl. It is also to be noted that a structural group can have more than one descriptive word or phrase in the art, for example, heteroaryloxyalkylcarbonyl can also be termed heteroaryloxyalkanoyl. Such combinations are used above in the description of the compounds and compositions of this invention and further examples are described below. The following list is not intended to be exhaustive or drawn out but provide further illustrative examples of such words or phrases.
As utilized herein, the term xe2x80x9calkylxe2x80x9d, alone or in combination, means a straight-chain or branched-chain alkyl radical containing 1 to about 12 carbon atoms, preferably 1 to about 10 carbon atoms, and more preferably 1 to about 6 carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like.
The term xe2x80x9calkenylxe2x80x9d, alone or in combination, means a straight-chain or branched-chain hydrocarbon radical having one or more double bonds and containing 2 to about 12 carbon atoms preferably 2 to about 10 carbon atoms, and more preferably, 2 to about 6 carbon atoms. Examples of suitable alkenyl radicals include ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, decenyl and the like.
The term xe2x80x9calkynylxe2x80x9d, alone or in combination, means a straight-chain hydrocarbon radical having one or more triple bonds and containing 2 to about 12 carbon atoms, preferably 2 to about 10 carbon atoms, and more preferably, 2 to about 6 carbon atoms. Examples of alkynyl radicals include ethynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.
The term xe2x80x9ccarbonylxe2x80x9d, alone or in combination, means a xe2x80x94C(xe2x95x90O)xe2x80x94 group wherein the remaining two bonds (valences) can be independently substituted. The term xe2x80x9cthiolxe2x80x9d or xe2x80x9csulfhydrylxe2x80x9d, alone or in combination, means a xe2x80x94SH group. The term xe2x80x9cthioxe2x80x9d or xe2x80x9cthiaxe2x80x9d, alone or in combination, means a thiaether group; i.e., an ether group wherein the ether oxygen is replaced by a sulfur atom.
The term xe2x80x9caminoxe2x80x9d, alone or in combination, means an amine or xe2x80x94NH2 group whereas the term mono-substituted amino, alone or in combination, means a substituted amine xe2x80x94N(H) (substituent) group wherein one hydrogen atom is replaced with a substituent, and disubstituted amine means a xe2x80x94N(substituent)2 wherein two hydrogen atoms of the amino group are replaced with independently selected substituent groups.
Amines, amino groups and amides are compounds that can be designated as primary (Ixc2x0), secondary (IIxc2x0) or tertiary (IIIxc2x0) or unsubstituted, mono-substituted or di-substituted depending on the degree of substitution of the amino nitrogen. Quaternary amine (ammonium)(IVxc2x0) means a nitrogen with four substituents [xe2x80x94N+(substituent)4] that is positively charged and accompanied by a counter ion, whereas N-oxide means one substituent is oxygen and the group is represented as [xe2x80x94N+(substituent)3xe2x80x94Oxe2x88x92]; i.e., the charges are internally compensated.
The term xe2x80x9ccyanoxe2x80x9d, alone or in combination, means a xe2x80x94C-triple bond-N (xe2x80x94C/N) group. The term xe2x80x9cazidoxe2x80x9d, alone or in combination, means a xe2x80x94N-triple bond-N (xe2x80x94N/N) group. The term xe2x80x9chydroxylxe2x80x9d, alone or in combination, means a xe2x80x94OH group. The term xe2x80x9cnitroxe2x80x9d, alone or in combination, means a xe2x80x94NO2 group. The term xe2x80x9cazoxe2x80x9d, alone or in combination, means a xe2x80x94Nxe2x95x90Nxe2x80x94 group wherein the bonds at the terminal positions can be independently substituted.
The term xe2x80x9chydrazinoxe2x80x9d, alone or in combination, means a xe2x80x94NHxe2x80x94NHxe2x80x94 group wherein the depicted remaining two bonds (valences) can be independently substituted. The hydrogen atoms of the hydrazino group can be replaced, independently, with substituents and the nitrogen atoms can form acid addition salts or be quaternized.
The term xe2x80x9csulfonylxe2x80x9d, alone or in combination, means a xe2x80x94SO2xe2x80x94 group wherein the depicted remaining two bonds (valences) can be independently substituted. The term xe2x80x9csulfoxidoxe2x80x9d, alone or in combination, means a xe2x80x94SOxe2x80x94 group wherein the remaining two bonds (valences) can be independently substituted.
The term xe2x80x9csulfonylamidexe2x80x9d, alone or in combination, means a xe2x80x94SO2xe2x80x94Nxe2x95x90 group wherein the depicted remaining three bonds (valences) can be independently substituted. The term xe2x80x9csulfinamidoxe2x80x9d, alone or in combination, means a xe2x80x94SONxe2x95x90 group wherein the remaining three depicted bonds (valences) can be independently substituted. The term xe2x80x9csulfenamidexe2x80x9d, alone or in combination, means a xe2x80x94Sxe2x80x94Nxe2x95x90 group wherein the remaining three bonds (valences) can be independently substituted.
The term xe2x80x9calkoxyxe2x80x9d, alone or in combination, means an alkyl ether radical wherein the term alkyl is as defined above. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
The term xe2x80x9ccycloalkylxe2x80x9d, alone or in combination, means a cyclic alkyl radical that contains 3 to about 8 carbon atoms. The term xe2x80x9ccycloalkylalkylxe2x80x9d means an alkyl radical as defined above that is substituted by a cycloalkyl radical containing 3 to about 8, preferably 3 to about 6, carbon atoms. Examples of such cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
The term xe2x80x9carylxe2x80x9d, alone or in combination, means a 5- or 6-membered aromatic ring-containing moiety or a fused ring system containing two or three rings that have all carbon atoms in the ring; i.e., a carbocyclic aryl radical, or a heteroaryl radical containing one or more heteroatoms such as sulfur, oxygen and nitrogen in the ring(s). Exemplary carbocyclic aryl radicals include phenyl, indenyl and naphthyl radicals. Examples of such heterocyclic or heteroaryl groups are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, pyrrolyl, imidazolyl (e.g., imidazol-4-yl, 1-benzyloxycarbonylimidazol-4-yl, and the like), pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, furyl, tetrahydrofuryl, thienyl, triazolyl, oxazolyl, oxadiazoyl, thiazolyl, thiadiazoyl, indolyl (e.g., 2-indolyl, and the like), quinolinyl, (e.g., 2-quinolinyl, 3-quinolinyl, 1-oxido-2-quinolinyl, and the like), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, and the like), tetrahydroquinolinyl (e.g., 1,2,3,4-tetrahydro-2-quinolyl, and the like), 1,2,3,4-tetrahydroisoquinolinyl (e.g., 1,2,3,4-tetrahydro-1-oxo-isoquinolinyl, and the like), quinoxalinyl, xcex2-carbolinyl, 2-benzofurancarbonyl, benzothiophenyl, 1-, 2-, 4- or 5-benzimidazolyl, and the like.
An aryl ring group optionally carries one or more substituents selected from alkyl, alkoxy, halogen, hydroxy, amino, nitro and the like, such as phenyl, p-tolyl, 4-methoxyphenyl, 4-(tert-butoxy)phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl, 1-naphthyl, 2-naphthyl, and the like.
The term xe2x80x9caralkylxe2x80x9d, alone or in combination, means an alkyl radical as defined above in which one hydrogen atom is replaced by an aryl radical as defined above, such as benzyl, 2-phenylethyl and the like.
The term xe2x80x9caralkoxycarbonylxe2x80x9d, alone or in combination, means a radical of the formula xe2x80x94C(O)xe2x80x94Oxe2x80x94 aralkyl in which the term xe2x80x9caralkylxe2x80x9d has the significance given above. An example of an aralkoxycarbonyl radical is benzyloxycarbonyl.
The term xe2x80x9caryloxyxe2x80x9d means a radical of the formula aryl-Oxe2x80x94 in which the term aryl has the significance given above.
The terms xe2x80x9calkanoylxe2x80x9d or xe2x80x9calkylcarbonylxe2x80x9d, alone or in combination, means an acyl radical derived from an alkanecarboxylic acid, examples of which include acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, and the like.
The term xe2x80x9ccycloalkylcarbonylxe2x80x9d means an acyl group derived from a monocyclic or bridged cycloalkanecarboxylic acid such as cyclopropanecarbonyl, cyclohexanecarbonyl, adamantanecarbonyl, and the like, or from a benz-fused monocyclic cycloalkanecarboxylic acid that is optionally substituted by, for example, alkanoylamino, such as 1,2,3,4-tetrahydro-2-naphthoyl, 2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl.
The terms xe2x80x9caralkanoylxe2x80x9d or xe2x80x9caralkylcarbonylxe2x80x9d mean an acyl radical derived from an aryl-substituted alkanecarboxylic acid such as phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl, 4-methoxyhydrocinnamoyl and the like.
The terms xe2x80x9caroylxe2x80x9d or xe2x80x9carylcarbonylxe2x80x9d means an acyl radical derived from an aromatic carboxylic acid. Examples of such radicals include aromatic carboxylic acids, an optionally substituted benzoic or naphthoic acid such as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl, 4-(benzyloxycarbonyl)benzoyl, 1-naphthoyl, 2-naphthoyl, 6-carboxy-2 naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl, 3-hydroxy-2-naphthoyl, 3-(benzyloxyformamido)-2-naphthoyl, and the like.
The heterocyclic (heterocyclo) portion of a heterocyclocarbonyl, heterocyclooxycarbonyl, heterocycloalkoxycarbonyl, or heterocycloalkyl group or the like is a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle that contains one or more hetero atoms selected from nitrogen, oxygen and sulphur. Such a moiety can be optionally substituted on one or more carbon atoms by halogen, alkyl, alkoxy, oxo, and the like, and/or on a secondary nitrogen atom (i.e., xe2x80x94NHxe2x80x94) by alkyl, aralkoxycarbonyl, alkylcarbonyl, aryl or arylalkyl or on a tertiary nitrogen atom (i.e. xe2x95x90Nxe2x80x94) by oxido and that is attached via a carbon atom. The tertiary nitrogen atom with three substituents can also attached to form a N-oxide [xe2x95x90N(O)xe2x80x94] group.
The term xe2x80x9ccycloalkylalkoxycarbonylxe2x80x9d means an acyl group of the formula cycloalkylalkyl-Oxe2x80x94COxe2x80x94 wherein cycloalkylalkyl has the significance given above. The term xe2x80x9caryloxyalkanoylxe2x80x9d means an acyl radical of the formula aryl-O-alkanoyl wherein aryl and alkanoyl have the significance given above. The term xe2x80x9cheterocyclooxycarbonylxe2x80x9d means an acyl group having the formula heterocyclo-Oxe2x80x94COxe2x80x94 wherein heterocyclo is as defined above. The term xe2x80x9cheterocycloalkanoylxe2x80x9d is an acyl radical of the formula heterocyclo-substituted alkane carboxylic acid wherein heterocyclo has the significance given above. The term xe2x80x9cheterocycloalkoxycarbonylxe2x80x9d means an acyl radical of the formula heterocyclo-substituted alkane-Oxe2x80x94COxe2x80x94 wherein heterocyclo has the significance given above. The term xe2x80x9cheteroaryloxycarbonylxe2x80x9d means an acyl radical represented by the formula heteroaryl-Oxe2x80x94COxe2x80x94 wherein heteroaryl has the significance given above.
The term xe2x80x9caminocarbonylxe2x80x9d alone or in combination, means an amino-substituted carbonyl (carbamoyl) group derived from an amino-substituted carboxylic acid (carboxamide) wherein the amino group can be a primary or secondary amino (amido nitrogen) group containing substituents selected from hydrogen, and alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like.
The term xe2x80x9caminoalkanoylxe2x80x9d means an acyl group derived from an amino-substituted alkanecarboxylic acid wherein the amino group can be a primary or secondary amino group containing substituents independently selected from hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like.
The term xe2x80x9chalogenxe2x80x9d means fluoride, chloride, bromide or iodide. The term xe2x80x9chaloalkylxe2x80x9d means an alkyl radical having the significance as defined above wherein one or more hydrogens are replaced with a halogen. Examples of such haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and the like.
The term perfluoroalkyl means an alkyl group wherein each hydrogen has been replaced by a fluorine atom. Examples of such perfluoroalkyl groups, in addition to trifluoromethyl above, are perfluorobutyl, perfluoroisopropyl, perfluorododecyl and perfluorodecyl.
The term xe2x80x9caromatic ringxe2x80x9d in combinations such as substituted-aromatic ring sulfonamide, substituted-aromatic ring sulfinamide or substituted-aromatic ring sulfenamide means aryl or heteroaryl as defined above.
M utilized in the reaction Schemes that follow represents a leaving group such as halogen, phosphate ester or sulfate ester.
Schemes 1 through 5 illustrate chemical processes and transformations that can be useful for the preparation of compounds useful in this invention; i.e., compounds of formulas I-III, Ia-IIIa and Ib-IIIb. The groups R1 through R9 shown in the schemes are defined above.
These reactions can be carried out under a dry inert atmosphere such a nitrogen or argon if desired. Selected reactions known to those skilled in the art, can be carried out under a dry atmosphere such as dry air whereas other synthetic steps, for example, aqueous acid or base ester or amide hydrolysis, can be carried out under laboratory air. In addition, some processes of this invention can be carried out in a pressure apparatus at pressures above, equal to or below atmospheric pressure. The use of such an apparatus aids in the control of gaseous reagents such as hydrogen, ammonia, trimethylamine, methylamine, oxygen and the like. It can also help prevent the leakage of air or humidity into a reaction in progress. This discussion is not intended to be exhaustive as it is readily noted that additional or alternative methods, conditions, reactions or systems can be identified and used by a chemist of ordinary skill.
Step 1 in Scheme 1 illustrates conversion of a hydroxyl group into compound 2 with an activated carbon-M bond via hydroxyl activation or replacement to provide intermediates useful as electrophilic reagents or, when M is xe2x80x94SH, a product of this invention of formula I is formed. M usually represents leaving groups such as halides (Cl, Br, I), fluorides (aromatic) or sulfate esters such as tosylate (OTs), mesylate (OMs), triflate (OTs) and the like, or epoxides. The preparations of epoxides, sulfate esters or organic halides are well known in the art. M can also represent groups such as xe2x80x94SH (thiol) or, following treatment of a thiol with base or with a pre-formed salt, an xe2x80x94Sxe2x88x92 group. The non-thiols are prepared from the alcohols by standard methods such as treatment with HCl, HBr, thionyl chloride or bromide, phosphorus trihalide, phosphorus pentahalide, trifluoromethylsulfonyl chloride, tosylchloride or methanesulfonyl chloride and the like.
These reactions are usually carried out at a temperature of about xe2x88x9225xc2x0 C. to solvent reflux under an inert atmosphere such as nitrogen or argon. The solvent or solvent mixture can vary widely depending upon reagents and other conditions and can include polar or dipolar aprotic solvents as listed or mixtures of these solvents.
In some cases, amines such as triethyl amine, pyridine or other non-reactive bases can serve as reagents and/or solvents and/or co-solvents. In some instances, in these reactions and other reactions in these Schemes, protecting groups can be used to maintain or retain groups in other parts of a molecule(s) at locations that is(are) not desired reactive centers. Examples of such groups that the skilled person might want to maintain or retain include, amines, other hydroxyls, thiols, acids and the like. Such protecting groups can include acyl groups, arylalkyl groups, carbamoyl groups, ethers, alkoxyalkyl ethers, cycloalkyloxy ethers, arylalkyl groups, silyl groups including trisubstituted silyl groups, ester groups and the like. Examples of such protecting groups include acetyl, trifluoroacetyl, tetrahydropyran (THP), Benzyl, tert-butoxy carbonyl (BOC or TBOC), benzyloxycarbonyl (Z or CBZ), tert-butyldimethylsilyl (TBDMS) or methoxyethoxymethylene (MEM) groups. The preparation of such protected compounds as well as their removal is well known in the art.
The second step in Scheme 1 illustrates preparation of a sulfonamide 2. Sulfamidation reactions are conveniently carried out by reacting an amine with, for example, a sulfonyl chloride or sulfonic anhydride. A suitable solvent or mixture of solvents includes aprotic or dipolar aprotic solvents as defined below with examples being acetone, methylene chloride DMF, THF, tert-butylmethylether (tBME) or mixtures of such solvents. Usually such reactions are carried out under and inert or dry atmosphere at a temperature of from about xe2x88x9225xc2x0 C. to 40xc2x0 C. preferably at about 0xc2x0 C. A base for the scavenging of acid is usually also present with non-limiting examples being triethyl amine, pyridine, DBU, N-ethyl morpholine (NEM), sodium carbonate and the like. The sulfonyl chlorides are well know in the art and are commercially available or can be prepared by the reaction of a suitable organometallic reagent with sulfuryl chloride or sulfur dioxide followed by oxidation with a halogen such as chlorine. Grignard and alkyl lithium reagents are desirable organometallic reagents.
In addition, thiols can be oxidized to sulfonyl chlorides using chlorine and/or chlorine with water. Sulfonic acids are available by the oxidation of thiols, reaction of sulfur derivatives with organometallic reagents and the like and can be converted into sulfonyl chlorides by treatment with thionyl chloride, PCl5 and the like. They are also commercially available.
Many reactions or processes involve bases that can act as reactants, reagents, deprotonating agents, acid scavengers, salt forming reagents, solvents, co-solvents and the like. Bases that can be used include, for example, metal hydroxides such as sodium, potassium, lithium, cesium or magnesium hydroxide, oxides such as those of sodium, potassium, lithium, calcium or magnesium, metal carbonates such as those of sodium, potassium, lithium, cesium, calcium or magnesium, metal bicarbonates such as sodium bicarbonate or potassium bicarbonate, primary (Ixc2x0), secondary (IIxc2x0) or tertiary (IIIxc2x0) organic amines such as alkyl amines, arylalkyl amines, alkylarylalkyl amines, heterocyclic amines or heteroaryl amines, ammonium hydroxides or quaternary ammonium hydroxides. As non-limiting examples, such amines can include triethylamine, trimethylamine, diisopropylamine, methyldiisopropylamine, diazabicyclononane, tribenzylamine, dimethylbenzylamine, morpholine, N-methylmorpholine, N,Nxe2x80x2-dimethylpiperazine, N-ethylpiperidine, 1,1,5,5-tetramethylpiperidine, dimethylaminopyridine, pyridine, quinoline, tetramethylethylenediamine, diazabicyclononane and the like. Non-limiting examples of ammonium hydroxides, usually made from amines and water, can include ammonium hydroxide, triethyl ammonium hydroxide, trimethyl ammonium hydroxide, methyldiiospropyl ammonium hydroxide, tribenzyl ammonium hydroxide, dimethylbenzyl ammonium hydroxide, morpholinium hydroxide, N-methylmorpholinium hydroxide, N,Nxe2x80x2-dimethylpiperazinium hydroxide, N-ethylpiperidinium hydroxide, and the like. As non-limiting examples, quaternary ammonium hydroxides can include tetraethyl ammonium hydroxide, tetramethyl ammonium hydroxide, dimethyldiiospropyl ammonium hydroxide, benzymethyldiisopropyl ammonium hydroxide, methyldiazabicyclononyl ammonium hydroxide, methyltribenzyl ammonium hydroxide, N,N-dimethylmorpholinium hydroxide, N,N,Nxe2x80x2,Nxe2x80x2-tetramethylpiperazenium hydroxide, and N-ethyl-Nxe2x80x2-hexylpiperidinium hydroxide and the like.
Metal hydrides, amides or alcoholates such as calcium hydride, sodium hydride, potassium hydride, lithium hydride, aluminum hydride, diisobutylaluminum hydrice (DIBAL) sodium methoxide, potassium tert-butoxide, calcium ethoxide, magnesium ethoxide, sodium amide, potassium diisopropyl amide and the like can also be suitable reagents. Organometallic deprotonating agents such as alkyl or aryl lithium reagents such as methyl lithium, phenyl lithium, tert-butyl lithium, lithium acetylide or butyl lithium, Grignard reagents such as methylmagnesium bromide or methymagnesium chloride, organocadium reagents such as dimethylcadium and the like can also serve as bases for causing salt formation or catalyzing the reaction. Quaternary ammonium hydroxides or mixed salts are also useful for aiding phase transfer couplings or serving as phase transfer reagents. Pharmaceutically acceptable bases and be reacted with acids to form pharmaceutically acceptable salts of this invention. It should also be noted that optically active bases can be used to make optically active salts which can be used for optical resolutions.
Generally, reaction media can consist of a single solvent, mixed solvents of the same or different classes or serve as a reagent in a single or mixed solvent system. The solvents can be protic, non-protic or dipolar aprotic. Non-limiting examples of protic solvents include water, methanol (MeOH), denatured or pure 95% or absolute ethanol, isopropanol and the like. Typical non-protic solvents include acetone, tetrahydrofurane (THF), dioxane, diethylether, tert-butylmethyl ether (TBME), aromatics such as xylene, toluene, or benzene, ethyl acetate, methyl acetate, butyl acetate, trichloroethane, methylene chloride, ethylenedichloride (EDC), hexane, heptane, isooctane, cyclohexane and the like. Dipolar aprotic solvents include compounds such as dimethylformamide (DMF), dimethylacetamide (DMAc), acetonitrile, DMSO, hexamethylphosphorus triamide (HMPA), nitromethane, tetramethylurea, N-methylpyrrolidone and the like. Non-limiting examples of reagents that might be used as solvents or as part of a mixed solvent system include organic or inorganic mono- or multi-protic acids or bases such as hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, formic acid, citric acid, succinic acid, triethylamine, morpholine, N-methylmorpholine, piperidine, pyrazine, piperazine, pyridine, potassium hydroxide, sodium hydroxide, alcohols or amines for making esters or amides or thiols for making the products of this invention and the like.
Step 4 of Scheme 1 is sulfamidation of compound 1 where R2 can be hydrogen or as otherwise defined. The process of sulfamidation is discussed above in reference to Step 2. The product is the alcohol 4.
Scheme 1 shows in Step 5 the direct conversion of an alcohol such as compound 4 into a contemplated sulfur-containing compound, 5. A descriptive term for this process is activated azo coupling. The process can be carried out by reacting a phosphine such as triphenyl phosphine and an azo compound such as diisopropylaziodicarboxylate (DIAD) or diethylazodicarboxylate (DEAD), a starting alcohol and a thiolcarboxylic acid or dithiocarboxylic acid. The reaction is usually carried out under an inert atmosphere such as nitrogen or argon at about xe2x88x9240xc2x0 C. to about 50xc2x0 C. in an inert solvent such as methylene chloride, THF or the others listed above.
The thioester or dithioester [R9(Cxe2x95x90S)xe2x80x94] 5 is a compound of Formula II. Compound 5 can be hydrolyzed to form compound 8 in Scheme 1 or compounds 15 or 16 as shown in Scheme 4. Compound 8 is a compound of formula I. This hydrolysis can be carried out with bases such as a metal hydroxide (LiOH, NaOH, KOH), carbonate (Na2CO3, K2CO3) or a bicarbonate (NaHCO3). Examples of other hydrolytic reagents suitable for this reaction include alkoxides such as sodium methoxide, potassium ethoxide and the like, a thiolate such as sodium thiophenolate, potassium methanethiolate and the like or by hydrolytic exchange with an amine or ammonia.
These reactions can be carried out under an inert atmosphere such as helium, nitrogen or argon at temperatures of from about xe2x88x9250xc2x0 C. to about 100xc2x0 C. Temperatures from about 0xc2x0 C. to about 60xc2x0 C. are preferred. Solvents, pure or mixed, include water, alcohols especially for alcoholate hydrolysis or dipolar aprotic solvents such as acetonitrile, DMSO or DMF. Amine exchanges can occur under conditions as discussed above. In addition, the amine can serve if desired as the solvent or a co-solvent as, for example, when diethylamine, morpholine, dimethyl amine (in a pressure system) or piperidine, are used as exchange agents.
The preparation of compound 8 from compound 5 can also be carried out using reductive processes if desired. Useful reducing agents may include lithium aluminum hydride, aluminum hydride, DIBAL, potassium borohydride, sodium borohydride, lithium borohydride or a metal catalyzed hydrogenation with a system such as the employing a Rosenmund catalyst. Reductions of the hydride type are usually carried out at between 80xc2x0 C. and xe2x88x9280xc2x0 C. in non-polar aprotic solvents such as THF or ethers whereas hydrogenations with hydrogen gas require containers (hydrogenation bottles, Parr bombs, pressure kettles and the like) with protic or non-protic solvents or solvent mixtures at temperatures of between xe2x88x9220xc2x0 C. to 100xc2x0 C.
Conversion of compound 3 in Scheme 1 into the sulfur-containing compound 5 illustrates displacement of an electrophile by a nucleophile; i.e., the conversion of a intermediate containing our activated leaving group M or a derivative into a sulfur compound of this invention. This method of synthesis is commonly called bimolecular nucleophilic substitution. Solvolysis or SN1 reactions are also possible and, if desired, can be used to provide electrophilic substitutions to produce alcohols, ethers, amines, carboxylate esters and the like. The reagents that provide the above compounds via SN1 ractions are water, alcohols, amines and carboxylic acids.
The nucleophilic displacement (SN2) reaction can be used in Step 3 wherein group M is displaced by a thiol compound or the salt of a thiol compound to produce compounds of formula I (compound 8) or formula II (compound 5) directly or a compound of formula I via conversion of II into I. The diagramatically reverse procedure; i.e., synthesis of a compound of formula I followed by its conversion into a compound of formula II or formula III can also be accomplished. Either compounds of formula I or of formula II can be direct or non-direct intermediates in the preparation of compounds III (e.g. compound 6).
Compounds of formula III can be converted into a compound of either of formulas I or II with a thiol reagent. Non-limiting examples of thiol reagents or their salts useful for nucleophilic displacement reactions are hydrogen sulfide (H2S), sodium sulfide (NaSH), thiolacetic acid [HS(Cxe2x95x90O)CH3], sodium thiolacetate [NaS(Cxe2x95x90O)CH3], dithioacetic acid [HS(Cxe2x95x90S)CH3] and sodium dithiolacetate [NaS(Cxe2x95x90S)CH3]. A thiolate or other anion can be obtained from a preformed salt such as sodium sulfide or sodium thiolacetate or it can be formed in situ via addition of a base to an acid such as hydrogen sulfide or thiolacetic acid. The bases and solvents are discussed above. Preferred bases are those that are hindered or tertiary such that competition with a sulfur anion as a nucleophile in a two stage reaction is minimized, e.g., triethylamine, pyridine, DBU, DMAP and the like. A strong inorganic base or organometallic base can be used if desired.
The solvents, solvent mixtures or solvent/reagent mixtures discussed above are satisfactory but non-protic or dipolar aprotic solvents such as acetone, acetonitrile, DMF, acetonitrile and the like are examples of a preferred class. Bases can also be used as solvents as well as reagents. Mixtures of the above solvents or with a solvent and a base such as pyridine or triethylamine are also useful. These reactions are usually carried out under an inert atmosphere (nitrogen, argon) at temperatures varying from between about xe2x88x9210xc2x0 C. to about 80xc2x0 C. In many cases, room temperature is preferred due to cost or simplicity. Again, procedures involving nucleophilic substitution reactions are well know in the art and sulfur based anions are known to be excellent nucleophiles.
The oxidation/reduction sequence illustrated in Scheme 1 Step 6 and Step 7 is also well known in the art. In addition, in situ hydrolysis of compound 5 by base, preferably protic, reaction of the Cxe2x95x90W group with a organometallic reagent or its reductive removal can provide an xe2x80x94SH compound 8. The thiol compound preformed or formed in the reaction, can then be oxidized if desired using, for example, air, oxygen, ozone, hypohalide reagents, sodium plumbite, or other likely oxidation agents. Non-oxidizable solvents and a basic or slightly basic pH value are preferred but not required and the atmosphere of the reaction can be air or another inert gas mentioned above. Preferred temperature is 0xc2x0 C. to 40xc2x0 C., but lower or higher temperatures can be used.
Mixed disulfides (heterodimers) can be made if the starting materials have different structures or by reaction of compound 6 (when R2 is H) with different alkylating agents as is discussed below. Reversal of the process ex vivo requires reduction of the disulfide bond to the thiol of formula I (compound 8). Compound 5 is formed by acylation of compound 8 with a reagent such as a derivative of HO(Cxe2x95x90W)R9. Such a derivative can be an activated carbonyl compounds prepared using reagents well know in the art including the peptide and protein synthesis and amino acid coupling or conjugation art. Examples of such reagents are thionyl chloride, oxalyl chloride, phosphorus oxychloride, HOBT (hydroxybenzotriazole), isobutylchloroformate, carbodimide, azodicarboxylate compounds an the like all of which are well known and established in the art. Reduction of the disulfide to the corresponding thiol can be carried out by, for example, treatment with hydride reagents such as lithium aluminum hydride, aluminum hydride, DIBAL, metal borohydrides (Li+, Na+, K+, Ca++), sodium cyanoborohydride and the like.
The aminoalcohol compound 7 in Scheme 2 illustrates a special case example of compound 1 wherein R2 is hydrogen. This series of reactions using, for example, compound 7, permits sulfamidation by processes discussed above wherein one skilled in the art can produce examples of compound 4 where R2 is hydrogen. This intermediate or product can then be alkylated or otherwise substituted to produce compound 4 wherein R2 is other than hydrogen. Alkylating agents include compounds that contain groups that can be displaced by a nucleophile such as a sulfamic acid salt.
Compound 4 with R2=hydrogen is a sulfamic acid and, as such, can be treated with a base to form an anion. This anion can be reacted in an SN2 manner with an intermediate or reagent containing a group that can be displaced with such displaceable groups including such non-limiting examples as epoxide, chloride, bromide, iodide, tosylate, mesylate, triflate, mesylate and the like. Examples of such reagents or intermediates include benzyl bromide, methyl iodide, n-butyl chloride, isoamyl tosylate, N-chloroethylmorpholine, N-bromoethylpiperidine and the like.
The anion can also be reacted (acylated) with a carbonyl compound in an addition-elimination sequence to provide a N-carbonyl compound. Such acylated compounds might be reduced to desired intermediates or serve as protecting groups or both. The anion can be formed with the bases listed and discussed above if the affects of sulfamide structure on pKa are accommodated. Sodium carbonate, potassium carbonate, potassium methoxide or DMAP represent bases sufficiently strong that they can be used to deprotonate a sulfonamide such as 4. In some cases, the use of a strong base such as an organometallic base under argon in a aprotic solvent is desirable.
The reactions are normally carried out under an inert atmosphere at temperatures of from about 0xc2x0 C. to about 100xc2x0 C. using either protic or dipolar aprotic solvents or with solvent mixtures. The solvent mixtures can include reagents such as amine bases that can also serve as part of a solvent mixture. An alkylation or acylation reactions involving salt formation are examples of the type reaction wherein a non-participating group such as a hydroxly group hydroxyl group on compound 4 can be protected if desired by the skilled chemist.
A second process that can be used to place an R2 group a sulfonamide with at least one hydrogen atom is reductive amination. Treatment of compound 4 containing an active hydrogen on the nitrogen of the sulfamide with an aldehyde or ketone and a reducing agent such as LiAlH4, NaCNBH4, LiBH4, AlH4 or hydrogen in the presence of controlled activity metal catalyst may provide compounds with a R2 group. An intermediate in this reductive process can be an sulfimine, sulfimine derivative or a tautomer thereof. The reducing agent can be present in the initial reaction or the intermediate can be subsquently reduced, i.e., the intermdiate carbonylsulfamide compound can be isolatable or it may be reduced further directly. A sulfamide salt can also add to a carbonyl group (acylation) of an ester, amide, anhydride, acid halide, mixed anhydride or similar compound and then be reduced.
Step 4 in Scheme 2 involves the hydroxyl conversion step discussed in with regards to Step 1 in Scheme 1. Here again, protection of a non-reactive group can be desirable. Once the hydroxyl is converted into, for example, a halide or sulfate ester, the sulfamide can be alkylated or reductively alkylated to introduce the R2 group (Step 5) if such is desired. This produces compound 3 which can be treated with a nucleophile including xe2x80x94SH to produce compounds 5 or 8. Note, these are the same compounds as can be produced via the methods of Scheme 1.
Scheme 2 also illustrates the conversion of compound 4 into compound 5, compound 4 into compound 9 and compound 9 into compound 3. The former conversion is discussed above per Scheme 1. The preparation of Compound 9 illustrates the preparation of a sulfonamide compound where R2 is hydrogen and M is a leaving group (activated intermediate).
The hydroxyl conversion process is well discussed above under Step 1 of Scheme 1. In this case, protection of groups that one does not wish to participate in a reaction or process can be useful. The use of reagents that convert hydroxyl groups into halide type leaving groups is preferred. Examples of such agents include hydrogen bromide, hydrogen chloride, hydrogen iodide, hydrobromic acid, hydrochloric acid or hydriodic acid. Agents that can convert a sulfonamide nitrogen-hydrogen bond into a nitrogen-halogen bond such as sodium hypochlorite can serve as a method of protecting the sulfonamide from further substitution on nitrogen. The halogen is removable when desired by reduction.
Once formed, compound 9 can be alkylated or acylated by processes as discussed for Step 2 in this Scheme to provide compound 3. Compound 3 can be converted into a compound of this invention of formula I or formula II (compound 5) via a nucleophilic or electrophilic substitution process as illustrated in Step 6. These processes and reactions are discussed above.
An alternative synthetic process strategy wherein one starts with an alcohol or protected alcohol intermediate substituted with an M leaving group is illustrated in Scheme 3. Conversion of compound 10 into compound 7 or compound 11 or a protected derivative is accomplished by amination at the carbon-M bond with a ammonia or a Ixc2x0 amine or derivative.
Amination can be a nucleophilic substitution process wherein the nucleophile is an amine, amine anion or other amine derivative. If an amine is the reagent desired, one can treat compound 10 directly with the amine at temperatures of from about xe2x88x9260xc2x0 C. to reflux temperature in protic, non-protic or dipolar aprotic solvents under an inert atmospheres or air. Protic solvents can include water wherein the reagent is usually an amine hydroxide such as ammonium hydroxide, benzylamine hydroxide and the like. Amine hydroxides are discussed above. Solvents that can react with amines such as ethyl acetate or acetone are not to be used. A pressure containment system or a low temperature system can be used for gaseous amines such as ammonia, methyl amine ethyl amine and the like. For example, reactions with or in ammonia can be run in liquid ammonia at a temperature of about xe2x88x9233xc2x0 C. The SN2 reaction can also be carried out with an metal-amine salt such as sodium amide, calcium amide, potassium metylamide and the like.
Following synthesis of the alcohol-amine compound 7 or 11 or a protected derivative thereof, one can add the N-substituent R2 by reductive amination or alkylation processes as discussed above. Compound 7 represents compounds where R2 is hydrogen whereas compound 11 represents compounds wherein R2 is any other group described earlier in this specification.
Step 3 in this sequence illustrates conversion of the unprotected alcohol group into the sulfur compound 12, which can then be converted into 5, which is a sulfonamide of this invention if formula II. Step 5 shows conversion of the M-substituted carbinol 10 into the sulfur compound 13 via a before-discussed activated azo procedure as in Step 3. Compound 13 can then be treated in Step 6 as with Step 1 to convert the M-carbon bond in compound 13 into a carbon-nitrogen bond to produce compounds 12 or 14 wherein R2 is either hydrogen (compound 14)or not hydrogen (compound 12). When this product is compound 14 and R2 is hydrogen, it can be converted into compound 12 by alkylation or reductive alkylation processes of Step 7 using the methods of Step 2.
Scheme 4 presents an alternative synthetic route to the compounds of this invention such as compounds 5, 15 or 16. The amine R2NH2 is reacted with a sulfonamide forming reagent such as a sulfonyl chloride under sulfamidation conditions to provide a sulfonamide. The sulfonamide can have two hydrogen atoms on the nitrogen of the sulfonamide group or it can have one nitrogen-carbon bond valence be occupied by a group R2. In the latter case, the sulfonamide can be alkylated (Step 3) by processes discussed above using compound 13 as the electrophile. Compound 13 was prepared in Scheme 3.
The product of this alkylation is compound 5, which is a sulfur compound of formula II of this invention. Hydrolysis of compound 5 can provide compound 16, which is a compound of formula I discussed above.
Step three displays the same process as Step 1 except that the amine is replaced by ammonia to provide an unsubstituted sulfonamide. This unsubstituted sulfonamide can be alkylated with, for example, compound 13 or compound 10, to produce sulfonamide compound 14 or sulfonamide compound 4. Alkylation of compound 14 by procedures illustrated above provides compound 5. Hydrolysis of compound 14 (Step 5) can produce compound 15 which is a compound of this invention of formula I.
An extended example Step 3 or Step 2 is provided by the procedure of Example 44. In this case, the amine can be R2NH2 with R2 being methyl followed by post sulfamidation alkylation with 2-iodobenzylchloride to produce a dialkylated sulfonamide that is subsequently converted into a thiol compound of this invention of formula IV. The inverse procedures can be carried out wherein the product of reaction with iodobenzylchloride or iodobenzylamine is the first sulfonamide that is then alkylated with methyl iodide. Conversion of this intermediate into the sulfur-containing product uses a cobalt complex with thiourea followed by reduction with sodium cyanoborohydride. This process is a useful alternative for the synthesis of aromatic sulfur compounds.
To further illustrate some of the general principles of synthesis of the compounds of this invention, Scheme 5 presents the preparation of the product of Example 41C. The carbinol amine a was treated with the sulfonyl chloride b under sulfamidation conditions to produce sulfonamide compound c. The reaction was carried out under nitrogen in THF and water as co-solvents and with triethylamine as the base to act a the product hydrochloric acid scavenger. The reaction temperature was about 0xc2x0 C. in an ice bath.
The sulfonamide c in which R2 is H was alkylated with methyl iodide to produce the product d wherein R2 is methyl. The solvent for this reaction was DMF with potassium carbonate base being suspended/dissolved therein under an atmosphere of nitrogen. The reaction mixture including the methyl iodide was maintained at room temperature.
Nucleophilic displacement of fluoride with an (ArSxe2x80x94)xe2x88x92 anion from the substituted aryl group on the sulfonamide was the next step carried out to produce compound e. Here, compound d was dissolved in DMF solvent followed by cesium carbonate and thiophenol. The reaction mixture was stirred for about 15 hours at about 70xc2x0 C. under nitrogen to produce the ArS-substituted aromatic N-methyl sulfonamide compound e.
This alcohol was then converted via the activated azo coupling procedure into the sulfur compound f, which is a compound, useful in a process of this invention. This reaction was carried out at 0xc2x0 C. in THF under nitrogen. The reagents triphenylphosphine and diethyldiazodicarboxylate were dissolved in the THF and thiolacetic acid was added. The reaction was permitted to proceed for about one hour to yield compound f which is the product of Example 41B. Hydrolysis of compound f with sodium methoxide in methanol at room temperature for about one half hour provide compound g which is also the product of Example 41C. This product of this invention is a potent MMP-13 inhibitor with an IC50=0.002 xcexcM (2 nM).
Optically active compound isomers as well as mixed or non-optically active compound isomers are specifically intended to be included in this discussion. Examples of isomers are RS isomers, enantiomers, diastereomers, racemates, cis isomers, trans isomers, E isomers, Z isomers, syn-isomers, anti-isomers, tautomers and the like. Aryl, heterocyclo or heteroaryl tautomers, heteroatom isomers and ortho, meta or para substitution isomers are also included as isomers.
The chemical reactions described above are generally disclosed in terms of their broadest application to the preparation of the compounds useful in this invention. Occasionally, the reactions may not be applicable as described to a particular compound included within the disclosed scope or can be unsafe in a particular instance. In addition, some preparations can be more desirable than the alternatives due to cost or other economic considerations. The compounds for which this occurs are readily recognized by those skilled in the art. In all such cases, either the reactions can be successfully performed by conventional modifications known to those skilled in the art, e.g., by appropriate protection of interfering groups, by changing to alternative conventional reagents, by routine modification of reaction conditions, and the like, or other reactions disclosed herein or otherwise conventional, will be applicable to the preparation of the corresponding compounds of this invention. In all preparative methods, all starting materials are known or readily preparable from known starting materials. 
 
 
 
 